WO2013041651A1 - Nouvelles formes cristallines de rivaroxaban et procédés pour les préparer - Google Patents

Nouvelles formes cristallines de rivaroxaban et procédés pour les préparer Download PDF

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Publication number
WO2013041651A1
WO2013041651A1 PCT/EP2012/068589 EP2012068589W WO2013041651A1 WO 2013041651 A1 WO2013041651 A1 WO 2013041651A1 EP 2012068589 W EP2012068589 W EP 2012068589W WO 2013041651 A1 WO2013041651 A1 WO 2013041651A1
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crystalline form
rivaroxaban
formula
preparation
slurrying
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PCT/EP2012/068589
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English (en)
Inventor
Nicolas Tesson
Llorenç RAFECAS JANÉ
Lydia Cárdenas Romaña
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Enantia, S.L.
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Publication of WO2013041651A1 publication Critical patent/WO2013041651A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to novel crystalline forms of rivaroxaban. It also relates to a process of preparing said polymorphic forms and their conversion into other crystalline forms.
  • Rivaroxaban is the generic name of compound 5-chloro-/V- ⁇ [(5S)-2-oxo-3-[4- (3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl ⁇ thiophene-2-carboxamide, the chemical structure of which is the following:
  • Rivaroxaban is currently used as anti-thrombotic agent. It was first disclosed in document WO 01/47919. The preparation of rivaroxaban as described in example 44 of this patent application is shown in the scheme below:
  • the above route of synthesis comprises the reaction of 4-(4-aminophenyl)-3- morpholinone and 2-[(2S)-2-oxiranylmethyl]-1 HJsoindol-1 ,3(2H)-dione to yield an aminoalcohol, which is subsequently converted into an aminoalcohol
  • rivaroxaban corresponds to a crystal modification which is designated as form I according to document WO 2007/039132 (filed by the same applicant).
  • Document WO 2007/039132 discloses further crystalline forms of rivaroxaban as well as an amorphous form of rivaroxaban.
  • the disclosed polymorphic forms are referred to as: rivaroxaban form II (m.p.
  • transition point 195°C; example 2
  • rivaroxaban form III transition point: 127°C; example 3
  • rivaroxaban hydrate containing about 4% of water; example 4
  • rivaroxaban NMP solvate containing about 18.5% of N-methylpyrrolidone; example 5
  • rivaroxaban inclusion compound with THF containing about 5-7% of tetrahydrofuran, example 6
  • WO 2007/039132 also describes the preparation of rivaroxaban form III in example 3. This process also uses a huge amount of solvent (832 total volumes with respect to the starting material) and, therefore, is not suitable for industrialization.
  • Another crystalline form of rivaroxaban is also described in document WO 2010/075631 .
  • This crystalline form which is referred to as form APO-A is characterized by an X-ray diffraction pattern comprising a peak at 39.12 or 34.60 degrees two-theta. According to the description, this crystalline form provides for reduced residual organic solvent in the crystalline form when compared to other polymorphic forms of rivaroxaban.
  • Rivaroxaban form I as described in WO 01/47919 is the most stable form of rivaroxaban and is very insoluble in water and in most industrial solvents. Thus, the complete dissolution of this crystalline form requires large amounts of solvents, and should be avoided in an industrial process.
  • the inventors have found that the slurrying of rivaroxaban form I in a mixture of an organic solvent and an acid furnish new crystal forms that can be used to obtain rivaroxaban form II and rivaroxaban form III (both as defined in WO
  • the process of the present invention overcomes the disadvantages of the prior art since it uses much lower amounts of solvent, preferably not higher than 20 volumes; the solvents and acids are industrially applicable and cheap; and the process shows a good reproducibility.
  • an aspect of the present invention relates to a process for the preparation of rivaroxaban of formula (I)
  • the crystalline form II has an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 12.8, 17.7, 18.1 , 18.4, 18.9, 19.9, 20.8, 21 .6, 22.0, 22.9, 24.0, 26.0, 26.4, 26.6, 27.1 , 27.5, 31 .0, and 31 .5 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A);
  • the crystalline form B2 has an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 7.1 , 14.2, 17.5, 19.8, 20.0, 21 .4, 24.1 , 24.5, 27.0, 28.7, 30.6, 39.8, 40.9, and 45.1 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A); and
  • the crystalline form E has an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 14.5, 18.2, 19.2, 20.2, 20.8, 21 .9, 24.7, 28.1 , and 31 .9 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • Another aspect of the invention relates to rivaroxaban of formula (I) in the crystalline form B2, having an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 7.1 , 14.2, 17.5, 19.8, 20.0, 21 .4, 24.1 , 24.5, 27.0, 28.7, 30.6, 39.8, 40.9, and 45.1 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • Another aspect of the invention relates to rivaroxaban of formula (I) in the crystalline form E, having an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 14.5, 18.2, 19.2, 20.2, 20.8, 21 .9, 24.7, 28.1 , and 31 .9 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • Another aspect of the invention relates to a process for the preparation of rivaroxaban of formula (I) in the crystalline form III comprising drying rivaroxaban of formula (I) in the crystalline form B1 at a temperature from 40°C to 100°C; wherein :
  • the crystalline form III has an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 19.2, 19.7, 19.9, 23.3, 23.8, 24.3, 28.3, and 31 .2 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A); and the crystalline form B1 has an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 7.1 , 14.2, 17.7, 19.7, 19.8, 20.1 , 21 .5, 24.2, 24.6, 27.2, 28.8, 40.0, 40.9, and 45.4 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • Another aspect of the invention relates to rivaroxaban of formula (I) in the crystalline form B1 having an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 7.1 , 14.2, 17.7, 19.7, 19.8, 20.1 , 21 .5, 24.2, 24.6, 27.2, 28.8, 40.0, 40.9, and 45.4 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • Another aspect of the invention relates to a process for the preparation of rivaroxaban of formula (I) in the crystalline form B1 as defined above comprising:
  • Another aspect of the invention relates to a process for the preparation of rivaroxaban of formula (I) in the crystalline form B1 as defined above comprising washing rivaroxaban of formula (I) in the crystalline form B2 with water; wherein the crystalline form B2 is as defined above.
  • FIG. 1 shows the X-ray powder diffraction pattern (intensity (counts) vs.
  • FIG. 2 shows the FTIR spectrum of rivaroxaban of formula (I) in the crystalline form B2.
  • FIG. 3 shows the X-ray powder diffraction pattern (intensity (counts) vs.
  • FIG. 4 shows the FTIR spectrum of rivaroxaban of formula (I) in the crystalline form E.
  • FIG. 5 shows the X-ray powder diffraction pattern (intensity (counts) vs.
  • FIG. 6 shows the FTIR spectrum of rivaroxaban of formula (I) in the crystalline form B1 .
  • the invention provides a process suitable for
  • Rivaroxaban form I is defined in WO 2007/039132 by having peak maxima at 4082, 4142, 4170, 4228, 4299, 4376, 4429, 4479, 4633, 4791 , 4877, 4907, 5081 , 5760, 5885, 6002, 6441 , 6564, 8473, and 8833 in the near infrared (NIR) spectrogram. It is also characterized by having a melting point of 230°C.
  • This crystalline form I has an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 9.0, 12.0, 14.3, 16.5, 17.4, 18.0, 19.5, 19.9, 21 .7, 22.5, 23.3, 24.1 , 24.7, 25.6, 26.6, 30.1 , and 31 .8 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A). Rivaroxaban form I may be obtained by the process described in WO 01/47919.
  • Rivaroxaban form II is defined in WO 2007/039132 by having peak maxima at 4086, 4228, 4418, 4457, 4634, 4905, 5846, 591 1 , 6026, 6081 , and 6582 in the near infrared (NIR) spectrogram.
  • This crystalline form II has an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 12.8, 17.7, 18.1 , 18.4, 18.9, 19.9, 20.8, 21 .6, 22.0, 22.9, 24.0, 26.0, 26.4, 26.6, 27.1 , 27.5, 31 .0, and 31 .5 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • Rivaroxaban form III is defined in WO 2007/039132 by having peak maxima at 4080, 4218, 4329, 4398, 4606, 4891 , 5066, 6022, and 6072 in the near infrared (NIR) spectrogram.
  • the crystalline form III has an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 19.2, 19.7, 19.9, 23.3, 23.8, 24.3, 28.3, and 31 .2 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • the crystalline form II may be obtained from an intermediate crystalline form B2 or E by the following steps:
  • step a) is carried out at a temperature from -10°C to 40°C.
  • the temperature is from -10 to 5°C, when the starting product is rivaroxaban of formula (I) in the crystalline form B2.
  • the temperature is from -10°C to 40°C, more preferably from room temperature to 40°C, when the starting product is rivaroxaban of formula (I) in the crystalline form E.
  • room temperature refers to a temperature from 20°C to 25°C.
  • the mixture is stirred for a suitable period of time, which can be from 1 -22 hours, more preferably from 3 to 16 hours.
  • a suitable period of time which can be from 1 -22 hours, more preferably from 3 to 16 hours.
  • the reaction time can be optimized depending on the reaction temperature.
  • the amount of isopropanol used in the reaction may be from 5 to 20 volumes with respect to the starting material. In a preferred embodiment, the amount of isopropanol is 10 to 20 volumes. Thus, the amount of solvent used in this step is very significantly reduced in comparison with the prior art processes.
  • the process further comprises the additional step of seeding the slurry obtained in isopropanol with a previously obtained rivaroxaban of formula (I) in the crystalline form II.
  • the isolation of the crystalline form II can be normally performed by any suitable industrial isolation method, such as filtration or centrifugation.
  • the isolation of the crystalline form II comprises filtration, which can be performed, for instance, by using a sintered funnel of a suitable porosity.
  • the product is washed with isopropanol.
  • the process further comprises an additional step of drying the product isolated in step b). Drying may be achieved optionally under vacuum at a suitable temperature, preferably at room temperature.
  • the intermediate crystalline forms B2 and E can be obtained from the crystalline form I by slurrying the later crystalline form in a mixture of an organic solvent and an acid. Depending on the acid used, either form B2 or form E is obtained. Thus, the crystalline form B2 may be obtained by using an acid other than HNO 3 . The crystalline form E is obtained by using HNO 3 .
  • the intermediate rivaroxaban crystalline form B2 is obtained by previously:
  • step (ii) isolating the product obtained in step (i) to obtain rivaroxaban of formula (I) in the crystalline form B2.
  • the intermediate rivaroxaban crystalline form E is obtained by previously:
  • step (ii) isolating the product obtained in step (i) to obtain rivaroxaban of formula (I) in the crystalline form E.
  • the organic solvent may be a (CrC 6 )alcohol such as methanol, ethanol or isopropanol; a (C 3 -C 8 )ketone, such as acetone, methylethyl ketone or methylisobutylketone; a (Ci-C 6 )alkyl(Ci-C 6 )ester, such as ethyl acetate; a (C 3 -C 6 )amide, such as dimethylformamide, dimethylacetamide or N- methylpyrrolidone; a (C 3 -C 6 )ether such as tetrahydrofuran or dioxane; or a (C 6 -C 9 )aromatic solvent, such as toluene or xylene.
  • the reaction is carried out in a (CrC 6 )alcohol or a (C 6 -C 9 )aromatic solvent. More preferably, the reaction is carried out in
  • the acid used in the above processes is added at low temperature, more preferably from 0° to 5°C.
  • This low temperature may be optionally maintained for a short period of time, e.g., 10 min.
  • the temperature is preferably raised to room temperature and left stand for a suitable period of time, which can be from 1 -3 hours, more preferably 1 .5 hours.
  • the acid used in the preparation of the crystalline form B2 may be organic or inorganic with the proviso that it is other than HNO 3 .
  • suitable inorganic acids include HCI and H 3 PO 4 .
  • suitable organic acids include formic acid and acetic acid.
  • the acid is an inorganic acid other than HNO 3 .
  • the acid is HCI.
  • the acid is concentrated aqueous HCI (generally 35-37%).
  • the HNO 3 used for the preparation of the crystalline form E is aqueous HNO 3 .
  • aqueous HNO 3 By way of example 5M, 8M, 10M, or 65% aqueous HNO 3 solutions may be used for the preparation of the crystalline form E.
  • the amount of solvent used in the reaction above for the preparation of both the crystalline forms B2 or E may be from 5 to 15 volumes with respect to the starting material, and the amount of acid may be from 1 to 15 volumes, preferably from 2.5 to 15 volumes, more preferably from 5 to 15 volumes, with respect to the starting material.
  • the amount of solvent used in this step is very significantly reduced in comparison with the prior art processes.
  • the processes for the preparation of the crystalline forms B2 and E comprise the additional step of seeding the slurry obtained in the mixture organic solvent/acid with the corresponding crystalline form (B2 or E).
  • the isolation of the crystalline form B2 or crystalline form E can be normally performed by any suitable industrial isolation method, such as filtration or centrifugation.
  • the isolation comprises filtering the product obtained, for instance, the filtration can be performed by using a sintered funnel of a suitable porosity; and optionally washing with an organic solvent.
  • the organic solvent used for the washing can be an organic solvent as described above.
  • the solvent used for the washing is a (CrC 6 )alcohol or a (C 6 -C 9 )aronnatic solvent, more preferably methanol or toluene. More preferably, the solvent used for the washing is the same solvent used for slurrying rivaroxaban of formula (I) in the crystalline form I.
  • the intermediate crystalline form B2 or E obtained is dried.
  • Drying may be achieved optionally under vacuum at a suitable temperature, preferably at a temperature from room temperature to 40°C.
  • rivaroxaban of formula (I) in the crystalline form B2 is isolated and dried without any washing step.
  • rivaroxaban of formula (I) in the crystalline form E is dried after a washing step with methanol or toluene.
  • a process for the preparation of rivaroxaban of formula (I) in the crystalline form III also forms part of the invention.
  • This process comprises drying rivaroxaban of formula (I) in a crystalline form B1 at a temperature from 40°C to 100°C, preferably from 40°C to 70°C, and more preferably at 40°C.
  • the drying is carried out under vacuum.
  • the drying time can be optimized depending on the drying temperature.
  • the intermediate rivaroxaban crystalline form B1 used in the above process is obtained by previously:
  • step (b) isolating the product obtained in step (a) to obtain rivaroxaban of formula (I) in the crystalline form B1.
  • the amount of water used in the reaction may be from 5 to 20 volumes with respect to the starting material, although it can also be performed in higher amounts such as 30 volumes.
  • this step is carried out at a temperature from 0° to room temperature, more preferably, at room temperature.
  • the mixture is stirred for a suitable period of time, which can be from 1 -22 hours, more preferably from 3 to 16 hours.
  • the isolation of the crystalline form B1 can be normally performed by any suitable industrial isolation method, such as filtration or centrifugation.
  • the isolation comprises filtration, which can be performed, for instance, by using a sintered funnel of a suitable porosity.
  • the product is washed with water. After washing, the product can be dried optionally under vacuum at a suitable temperature, preferably at a temperature lower than 35°C, more preferably at room temperature.
  • the intermediate rivaroxaban crystalline form B1 may be directly obtained by washing rivaroxaban of formula (I) in the crystalline form B2 with water. This process forms also part of the present invention.
  • the amount of water used for the washing may be from 2 to 15 volumes with respect to the starting material.
  • the product can be dried optionally under vacuum at a suitable temperature, preferably at a temperature lower than 35°C, more preferably at room temperature.
  • the intermediate rivaroxaban crystalline form B2 in the preparation of rivaroxaban of formula (I) in the crystalline form III, the intermediate rivaroxaban crystalline form B2, and which is subsequently slurried in or washed with water, is obtained by previously:
  • step (ii) isolating the product obtained in step (i) to obtain rivaroxaban of formula (I) in the crystalline form B2.
  • step (i) above relating to the preparation of the crystalline form B2 to be used in the preparation of form III is carried out in the same conditions and preferences as the ones already described in the corresponding embodiment relating to the preparation of the crystalline form B2 to be used in the preparation of the crystalline form II.
  • the isolation of the crystalline form B2 can be normally performed by any suitable industrial isolation method, such as filtration or centrifugation as previously mentioned.
  • the intermediate rivaroxaban crystalline form E is obtained by previously:
  • step (ii) isolating the product obtained in step (i) to obtain rivaroxaban of formula (I) in the crystalline form E.
  • step (i) above relating to the preparation of the crystalline form E to be used in the preparation of form III is carried out in the same conditions and preferences as the ones already described in the corresponding embodiment relating to the preparation of the crystalline form E to be used in the preparation of the crystalline form II.
  • the isolation of the crystalline form E can be normally performed by any suitable industrial isolation method, such as filtration or centrifugation as previously mentioned.
  • any suitable industrial isolation method such as filtration or centrifugation as previously mentioned.
  • the crystalline forms B1 , B2, and E of rivaroxaban also form part of the invention and have been characterized by several techniques such as proton nuclear magnetic resonance ( 1 H-NMR), Fourier Transform Infrared (FTIR), Differential Scanning Calorimetry (DSC), Thermogravimetric (TGA), X-ray powder diffraction (XRPD).
  • the crystalline forms B1 and B2 are hydrates having similar XRPD patterns. However, the crystalline form B1 contains a lower amount of water in comparison with the crystalline form B2.
  • the crystalline form E appears to be a nitric acid solvate.
  • Different crystalline forms can have different characteristics, and offer certain advantages, for example with regard to stability, solubility or bioavailability, which allows for improving the characteristics of the pharmaceutical formulations of the active ingredients, since some forms are more adequate for one type of formulation, and other forms for other different formulations. Furthermore, depending on the therapeutic indications, one or another pharmaceutical formulation may be preferred.
  • rivaroxaban of formula (I) in the crystalline form B1 and B2 are stable crystalline forms in the conditions of storage (no modifications were observed by XRPD after several months of storage at room temperature). Furthermore, the crystalline forms B1 and B2 (B2 is converted to B1 in water) show a better solubility in water than the crystalline stable form I.
  • the crystal form E is a very stable crystal form, which allows an easy manipulation for the preparation of the crystalline forms B1 , II and III (no modifications observed by XRPD after several months of storage at room temperature).
  • rivaroxaban of formula (I) in the crystalline form B1 shows an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 7.1 , 12.3, 14.2, 17.7, 17.9, 19.7, 19.8, 20.1 , 20.6, 21 .5, 24.2, 24.6, 26.2, 27.2, 28.8, 30.1 , 31 .7, 33.6, 37.3, 37.8, 40.0, 40.9, and 45.4 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • the crystalline form B1 shows an X-ray powder diffraction pattern comprising 2 ⁇ angle values substantially according to Table 3. In another preferred embodiment, the crystalline form B1 shows an X-ray powder diffraction pattern substantially according to FIG. 5. In another preferred embodiment, the crystalline form B1 shows a FTIR spectrum substantially according to FIG. 6.
  • the crystalline form B1 is more soluble in water than form I, as it is also the case of the crystalline form II.
  • rivaroxaban belongs to the Biopharmaceutics Classification System (BCS) class II, an improvement of the solubility should increase its bioavailability.
  • the inventors have found that the crystalline form B1 is more stable than the crystalline form II.
  • rivaroxaban hydrate form B1 remained stable in water at room temperature even after 8h, while a slurrying of rivaroxaban form II in water at room temperature, rendered a partial transformation in the stable form rivaroxaban form I after 1 h.
  • the present invention also relates to rivaroxaban of formula (I) in the crystalline form B1 for use in the treatment and/or prophylaxis of diseases, preferably thromboembolic diseases and/or thromboembolic complications.
  • rivaroxaban of formula (I) in the crystalline form B1 for the manufacture of a medicament for the treatment and/or prophylaxis of diseases, preferably thromboembolic diseases and/or thromboembolic complications.
  • the present invention also relates to a method for the treatment and/or prophylaxis of diseases, preferably thromboembolic diseases and/or thromboembolic complications, comprising administering a pharmaceutically effective amount of rivaroxaban of formula (I) in the crystalline form B1 , together with pharmaceutically acceptable excipients or carriers, in a subject in need thereof, including a human. Further, the invention also relates to rivaroxaban of formula (I) in the intermediate crystalline form B2.
  • the crystalline form B2 shows an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 7.1 , 14.2, 17.5, 17.8, 19.8, 20.0, 21 .4, 24.1 , 24.5, 24.9, 26.2, 27.0, 28.7, 30.1 , 30.6, 32.4, 39.8, 40.9, and 45.1 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • the crystalline form B2 shows an X-ray powder diffraction pattern comprising 2 ⁇ angle values substantially according to Table 1 . In another preferred embodiment, the crystalline form B2 shows an X-ray powder diffraction pattern substantially according to FIG. 1 . In another preferred embodiment, the crystalline form B2 shows a FTIR spectrum substantially according to FIG. 2.
  • the invention also relates to rivaroxaban of formula (I) in the intermediate crystalline form E.
  • the crystalline form E shows an X-ray powder diffraction pattern comprising 2 ⁇ angle values at 14.5, 18.2, 18.4, 19.2, 19.6, 20.2, 20.8, 21 .9, 23.2, 23.7, 23.9, 24.7, 26.1 , 26.4, 28.1 , 28.4, 29.3, 30.3, 31 .9, 33.8, 34.2, 39.9, and 41 .1 ⁇ 0.1 measured in an X-ray diffractometer with Cu Ka radiation (1 .5418 A).
  • the crystalline form E shows an X-ray powder diffraction pattern comprising 2 ⁇ angle values substantially according to Table 2.
  • the crystalline form E shows an X-ray powder diffraction pattern substantially according to FIG. 3.
  • the crystalline form E shows a FTIR spectrum substantially according to FIG. 4.
  • the crystalline form E has a melting point of 148.2 °C.
  • the present invention also provides processes for preparing the novel crystalline forms of the invention B1 , B2 and E.
  • the crystalline form B1 may be prepared starting from the crystalline form I; the crystalline forms B2 or E; or from the crystalline form III.
  • the present invention provides a process for the preparation of the crystalline form B1 comprising:
  • the latter process for the preparation of form B1 above is carried out in the same conditions and preferences as the ones already described in the corresponding embodiment relating to the preparation of the crystalline form B1 to be used in the preparation of the crystalline form III.
  • the present invention also provides a process for the preparation of rivaroxaban of formula (I) in the crystalline form B1 comprising washing rivaroxaban of formula (I) in the crystalline form B2 with water. This washing step is carried out in the same conditions and preferences as the ones already described in the corresponding embodiment of the process for the preparation of rivaroxaban of formula (I) in the crystalline form III.
  • the crystalline form B1 is dried after its isolation. Drying may be achieved optionally under vacuum at a suitable temperature, preferably at a temperature lower than 35°C, more preferably at room temperature.
  • the intermediate rivaroxaban crystalline form B2 is obtained by previously:
  • step (ii) isolating the product obtained in step (i) to obtain rivaroxaban of formula (I) in the crystalline form B2.
  • the intermediate rivaroxaban crystalline form E is obtained by previously:
  • step (ii) isolating the product obtained in step (i) to obtain rivaroxaban of formula (I) in the crystalline form E.
  • preparation of the crystalline form B1 comprising submitting the crystalline form III under humidity conditions, preferably in an atmosphere having at least 49% humidity, more preferably, at a temperature from 20-30°C and humidity of 49-100%.
  • the crystalline form B2 and form E may be prepared starting from the crystalline form I.
  • the present invention provides a process for the preparation of the crystalline form B2, which comprises:
  • the present invention also provides a process for the preparation of the nitric acid solvate form E, which comprises:
  • spectrometer equipped with a broadband probe ATB 1 H/19F/X of 5 mm. Spectra were acquired dissolving 5-10 mg of sample in 0.6 ml_ of deuterated solvent.
  • FTIR Fourier Transform Infrared
  • DSC Differential Scanning Calorimetry
  • thermogravimetric (TGA) analyses were recorded in a thermogravimetric analyzer Mettler TGA SDTA851 e . Samples of the products were weighed into a 70 ⁇ _ alumina crucible with a pinhole lid and was heated at 10 °C/min from 30 to 300 °C, under nitrogen (50 mL/min).
  • X-ray powder diffraction (XRPD) analyses were performed using a
  • Example 1 Slurrying in MeOH in the presence of concentrated HCI from rivaroxaban form I
  • rivaroxaban form I 150 mg, 0.34 mmol was added methanol (2.3 mL, 15 vol.) and was stirred for a few minutes. Then, hydrochloric acid 37% (2.3 mL, 15 vol.) was added dropwise at 0°C. The resultant suspension was stirred at room temperature for 1 .5 hours. The solid was filtered with a sintered funnel (porosity 4) and dried under vacuum at room temperature to give rivaroxaban of formula (I) in the crystalline form B2 as a pale yellow solid (145 mg, 89% approximated yield).
  • Example 2 Slurrying in MeOH in the presence of concentrated HCI from rivaroxaban form I
  • rivaroxaban form I (5.00 g, 1 1 .47 mmol) was added methanol (75 mL, 15 vol.) and was stirred for a few minutes. Then, hydrochloric acid 37% (75 mL, 15 vol.) was added dropwise at 0°C. The resultant suspension was seeded with rivaroxaban of formula (I) in the crystalline form B2 and was stirred at room temperature for 1 .5 hours. The solid was filtered with a sintered funnel (porosity 3) and dried under vacuum at room temperature to give rivaroxaban of formula (I) in the crystalline form B2 as an off-white solid (4.95 g, 92% approximated yield).
  • rivaroxaban form I (345 mg, 0.79 mmol) was added methanol (1 .7 mL, 5 vol.) and was stirred for a few minutes at 0°C. Then, hydrochloric acid 37% (3.45 mL, 10 vol.) was added dropwise at 0°C. The resultant suspension was stirred at room temperature for 1 .5 hours. The solid was filtered with a sintered funnel (porosity 4) and dried under vacuum at room temperature to give rivaroxaban of formula (I) in the crystalline form B2 as an off-white solid (330 mg, 88% yield).
  • Example 4 Slurrying in toluene in the presence of concentrated HCI from rivaroxaban form I
  • rivaroxaban form I (20 mg, 0.05 mmol) was added toluene (0.3 mL, 15 vol.) and was stirred for a few minutes at 0°C. Then, hydrochloric acid 37% (0.02 mL, 1 vol) was added dropwise at 0°C. The resultant two phases were stirred at room temperature for 1 .5 hours. The solid was filtered with a sintered funnel (porosity 4) and dried under vacuum at room temperature to give rivaroxaban of formula (I) in the crystalline form B2 as an off-white solid (20 mg, 93% approximated yield).
  • Rivaroxaban of formula (I) in the crystalline form B2 is characterized for two endothermic intense peaks corresponding to the water loss at an onset 71 .95°C (fusion enthalpy -191 .51 J/g) and the melting point at an onset 228.78 °C (fusion enthalpy -101 .13 J/g) and two exothermic sharp peaks corresponding to a polymorphic transformations at an onset 139.84 °C
  • TGA The TG analysis of rivaroxaban of formula (I) in the crystalline form B2 shows a weight loss at temperatures lower than the melting point. It corresponds to water loss (9.8%). A TGA of another batch of the same crystalline form gave results a little different (loss of water 8.4%) for the possibility of a water loss depending on the atmospheric conditions (but this loss of water in these conditions does not seem change the crystal form).
  • XRPD The XRPD pattern of rivaroxaban of formula (I) in the crystalline form B2 is shown in FIG. 1 . Table 1 shows the position (2theta angle (°)) and relative intensity (%) of the main peaks of the XRPD spectrum of FIG. 1 .
  • Example 5 Slurrying in MeOH from rivaroxaban form I in the presence of HNO, 65%
  • methanol 0.3 mL, 15 vol.
  • nitric acid 65% 0.3 mL, 15 vol.
  • the mixture was stirred at 0-5°C for 10 minutes and at room temperature for 1 .5 hours.
  • the solid was filtered with a sintered funnel (porosity 4) and dried under vacuum at room
  • Example 6 Slurrying in MeOH from rivaroxaban form I in the presence of HNO 3 _65%
  • rivaroxaban form I 300 mg, 0.69 mmol
  • methanol 4.5 mL, 15 vol.
  • the resultant suspension was stirred at 0-5°C for a few minutes and was seeded with rivaroxaban of formula (I) in the crystalline form E.
  • nitric acid 65% (1 .5 mL, 5 vol.) was added dropwise at 0-5°C.
  • the mixture was stirred at 0-5°C for 10 minutes and at room temperature for 1 .5 hours.
  • Example 7 Slurrying in MeOH from rivaroxaban form I in the presence of a 8M aqueous HNO ⁇ solution To an assay tube equipped with magnetic stirrer containing rivaroxaban form I (399 mg, 0.92 mmol) was added methanol (4 mL, 10 vol.).
  • the resultant suspension was stirred at 0-5°C for a few minutes and was seeded with rivaroxaban of formula (I) in the crystalline form E). Then, nitric acid 8M aqueous solution (2 mL, 5 vol.) was added dropwise at 0-5°C. The mixture was stirred at 0-5°C for 10 minutes and at room temperature for 1 .5 hours. The solid was filtered with a sintered funnel (porosity 4), washed with methanol (2 x 1 mL) and dried under vacuum at room temperature to give rivaroxaban of formula (I) in the crystalline form E as a white solid (435 mg, 95% yield).
  • Example 8 Slurrying in toluene from rivaroxaban form I in the presence of a 5M aqueous HNO solution
  • Rivaroxaban of formula (I) in the crystalline form E is characterized by an endothermic peak corresponding to the melting point with an onset at 148.21 °C (fusion enthalpy -19.86 J/g) followed by an exothermic sharp peak corresponding to a decomposition (decomposition enthalpy 46.95 J/g), measured by DSC analysis (10 °C/min)
  • TGA The TG analysis of rivaroxaban of formula (I) in the crystalline form E shows a weight loss at temperatures between the melting point and the decomposition of the sample. It corresponds to HNO 3 loss (8.9 %) but it is altered by the decomposition of RVB (the loss of 1 HNO3 molecule is supposed to be 12.6 %).
  • KF Rivaroxaban of formula (I) in the crystalline form E was dissolved in a mixture of acetonitrile with 1 % of dimethylformamide (20 mg/4 ml_). Three 0.79 mg samples of this solution were analyzed using the following reactants: Hydranal-Composite 5 (Riedel de Haen Ref. 34805), Hydranal Methanol Rapid (Riedel de Haen Ref. 37817) and Hydranal Water Standard 1 .0 (Riedel de Haen Ref. 34828 used to calculate the factor).
  • the KF analysis of rivaroxaban of formula (I) in the crystalline form E shows 0.06 % water. This is not a hydrate.
  • XRPD The XRPD pattern of rivaroxaban of formula (I) in the crystalline form E is shown in FIG. 3. Table 2 shows the position (2theta angle (°)) and relative intensity (%) of the main peaks of the XRPD spectrum of FIG. 3.
  • TITRATION A suspension of rivaroxaban of fornnula (I) in the crystalline form E (100 mg, 0.20 mmol) in water (5 mL) was stirred at room temperature for 3 hours. The resultant suspension was titrated with a 0.1 M NaOH aq. solution to determine the amount of HNO 3 in rivaroxaban of formula (I) in the crystalline form E. The amount of 0.1 M NaOH aq. solution used in the analysis corresponds with a rivaroxaban nitric acid solvate with 1 :1 stoichiometry.
  • Example 9 Humidity atmosphere from rivaroxaban form III To a crystallizer containing rivaroxaban form III (1 .37 g, 3.14 mmol) was submitted at atmosphere conditions (temperature 24.2-27.2 °C and humidity 49-65 %) over a period of 1 day. Rivaroxaban hydrate form B1 was obtained as a white solid (quantitative yield).
  • Example 10 Slurrying in water from rivaroxaban form B2
  • rivaroxaban of formula (I) in the crystalline form B2 25 mg, 0.05 mmol was added water (0.4 ml_, 16 vol.). The resultant suspension was stirred at room temperature for 4 hours. The solid was filtered with a sintered funnel (porosity 4), washed with water (3x0.2 ml_) and dried under moderate vacuum at room temperature to give rivaroxaban hydrate form B1 as a white solid (20 mg, 88 % approximated yield).
  • Example 1 1 Slurrying in water from rivaroxaban of formula (I) in the crystalline form E
  • Rivaroxaban hydrate form B1 is characterized for two endothermic intense peaks corresponding to the water loss at an onset 51 .90 °C (fusion enthalpy -157.78 J/g) and the melting point at an onset 222.35 °C (fusion enthalpy -90.15 J/g), two exothermic sharp peaks corresponding to a polymorphic transformations at an onset 143.64 °C (formation enthalpy 9.30 J/g) and at an onset 188.35 °C (formation enthalpy 9.1 1 J/g), measured by DSC analysis (10 °C/min).
  • TGA The TG analysis of rivaroxaban hydrate form B1 shows a weight loss at temperatures lower than the melting point. It corresponds to water loss (6.5%).
  • XRPD The XRPD pattern of rivaroxaban hydrate form B1 is shown in FIG. 5. Table 3 shows the position (2theta angle (°)) and relative intensity (%) of the main peaks of the XRPD spectrum of FIG. 5.
  • Example 12 Slurrying in water rivaroxaban of formula (I) in the crystalline form B2 To a round-bottom flask equipped with magnetic stirrer containing rivaroxaban hydrate B2 (3.01 g, 6.38 mmol) was added water (90 mL, 30 vol.). The resultant suspension was stirred at room temperature for 4 hours. The solid was filtered with a sintered funnel (porosity 4), washed with water (2x5 mL) and dried under vacuum at 40°C overnight to give rivaroxaban form III as a white solid (2.72 g, 98% approximated yield).
  • Example 13 Slurrying in MeOH in the presence of concentrated HCI from rivaroxaban form I and wash with water To a round-bottom flask equipped with magnetic stirrer containing
  • rivaroxaban form I 50 mg, 0.1 1 mmol
  • methanol 750 ⁇ _, 15 vol.
  • hydrochloric acid 37% 750 ⁇ _, 15 vol.
  • the resultant suspension was seeded with rivaroxaban of formula (I) in the crystalline form B2 and was stirred at room temperature for 1 .5 hours.
  • the solid was filtered with a sintered funnel
  • Example 14 Slurrying in water from rivaroxaban of formula (I) in the crystalline form E
  • Example 15 Slurrying in IPA rivaroxaban of formula (I) in the crystalline form B2
  • rivaroxaban of formula (I) in the crystalline form B2 (100 mg, 0.21 mmol) was added isopropanol (1 mL, 10 vol.). The resultant suspension was stirred at - 10°C for 16 hours. The solid was filtered with a sintered funnel (porosity 4), washed with cold isopropanol (2x0.2 mL) and dried under vacuum at room temperature to give rivaroxaban form II as a white solid (60 mg, 66% approximated yield).
  • Example 16 Slurrying in IPA rivaroxaban of formula (I) in the crystalline form B2
  • rivaroxaban of formula (I) in the crystalline form B2 (1 .00 g, 2.12 mmol) was added isopropanol (10 ml_).
  • the resultant suspension was seeded with rivaroxaban form II and was stirred at -10°C for 16 hours.
  • the solid was filtered with a sintered funnel (porosity 3), washed with cold isopropanol (2x0.3 ml_) and dried under vacuum at room temperature to give rivaroxaban form II as a white solid (886 mg, 96% approximated yield).
  • Example 17 Slurrying in IPA from rivaroxaban of formula (I) in the crystalline form E To an assay tube equipped with magnetic stirrer containing rivaroxaban of formula (I) in the crystalline form E (21 mg, 0.04 mmol) was added
  • Example 18 Slurrying in IPA from rivaroxaban of formula (I) in the crystalline form E

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne de nouvelles formes cristallines de rivaroxaban, en particulier le rivaroxaban de formule (I) dans la forme cristalline B1, la forme cristalline B2, la forme cristalline E. Elle concerne également un procédé de préparation desdites formes polymorphes et leur conversion en d'autres formes cristallines.
PCT/EP2012/068589 2011-09-22 2012-09-21 Nouvelles formes cristallines de rivaroxaban et procédés pour les préparer WO2013041651A1 (fr)

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CN104650058A (zh) * 2013-11-23 2015-05-27 天津市汉康医药生物技术有限公司 利伐沙班一水合物化合物
CN110655516A (zh) * 2018-06-29 2020-01-07 鲁南制药集团股份有限公司 一种抗凝血药物的晶型

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CN104211693B (zh) * 2014-08-07 2017-02-22 成都百裕制药股份有限公司 一种利伐沙班晶型及其制备方法与用途

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WO2001047919A1 (fr) 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine
WO2007039132A1 (fr) 2005-10-04 2007-04-12 Bayer Healthcare Ag Nouvelle forme polymorphe et forme amorphe de 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide
WO2010075631A1 (fr) 2008-12-31 2010-07-08 Apotex Pharmachem Inc Forme polymorphe de la 5-chloro-n-{[(5s)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phényl]oxa-zolidin-s-yl]méthyl}thiophène-2-carboxamide
WO2011012321A1 (fr) * 2009-07-31 2011-02-03 Krka, D.D., Novo Mesto Méthodes de cristallisation de rivaroxaban

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WO2001047919A1 (fr) 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Oxazolidinones substituees et leur utilisation dans le domaine de la coagulation sanguine
WO2007039132A1 (fr) 2005-10-04 2007-04-12 Bayer Healthcare Ag Nouvelle forme polymorphe et forme amorphe de 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophenecarboxamide
WO2010075631A1 (fr) 2008-12-31 2010-07-08 Apotex Pharmachem Inc Forme polymorphe de la 5-chloro-n-{[(5s)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phényl]oxa-zolidin-s-yl]méthyl}thiophène-2-carboxamide
WO2011012321A1 (fr) * 2009-07-31 2011-02-03 Krka, D.D., Novo Mesto Méthodes de cristallisation de rivaroxaban

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104650058A (zh) * 2013-11-23 2015-05-27 天津市汉康医药生物技术有限公司 利伐沙班一水合物化合物
CN110655516A (zh) * 2018-06-29 2020-01-07 鲁南制药集团股份有限公司 一种抗凝血药物的晶型
CN110655516B (zh) * 2018-06-29 2023-10-20 鲁南制药集团股份有限公司 一种抗凝血药物的晶型

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